Design, synthesis and bioevaluation of 1-indole-4-carboxamide derivatives as potent poly(ADP-ribose) polymerase-1 inhibitors

• Published in: RSC advances 2016-08, Vol.6 (84), p.8784-8796
• Main Authors: Xie, Zhouling, Chen, Yu, Xu, Pengfei, Zhou, Youli, Zhao, Qian, Jiao, He, Li, Zhiyu
• Format: Article
• ISSN: 2046-2069
• DOI: 10.1039/c6ra12591c

Two new series of 1 H -indole-4-carboxamide derivatives were designed and synthesized as potent PARP-1 inhibitors. These compounds were further evaluated for PARP-1 enzyme and cellular inhibitory activity, resulting in the identification of compound LX15 with superior potency against both the PARP-1 (IC 50 = 13 nM) and BRCA1 deficient cells (CC 50 = 0.98 M), and it is more potent than AG014699 . In addition, LX15 displayed excellent selectivity between the BRCA1 deficient cells and wild type MCF-7 cells (CC 50 = 0.98 M vs. CC 50 = 22 M). The studies of the mechanism indicated that LX15 significantly caused the accumulation of DNA double-strand breaks and impaired the cell-cycle progression in BRCA1 deficient cells. Moreover, LX15 exhibited reasonable PK profiles and significantly potentiated the efficacy of temozolomide ( TMZ ) in MCF-7 cells in vitro and the B16F10 murine melanoma model in vivo . All results indicated that LX15 could be a promising drug candidate for further study. LX15 is more potent than AG014699 in PARP-1 inhibitory activity and BRCA-1 deficient cell inhibitory activity. It is more effective than AG014699 in potentiating the antitumor activity of TMZ in vitro and in vivo .